Calcium release channel is a homotetramer with a subunit molecular weight of 500 kDa and is responsible for rapid release of calcium from sarcoplasmic reticulum as part of excitation-contraction coupling. Defects in this protein or the regulation of its activity produces the disease malignant hyperthermia. The three-dimensional structure of the skeletal muscle Ca2+-release channel in its open state is determined from electron micrographs of ice-embedded samples using angular reconstitution. In contrast to our reconstruction of the channel in its closed state, the density map of the channel driven towards its open state by the presence of Ca2+ and ryanodine, features a central opening in the transmembrane region, the likely passageway for Ca2+ ions from the sarcoplasmic reticulum to the cytosol. The opening of the channel is associated with significant mass translocations within the entire cytoplasmic region of the channel.